The present invention is directed to benzamidine derivatives and their pharmaceutically acceptable salts, which inhibit the enzyme, factor Xa, thereby being useful as anti-coagulants. It also relates to pharmaceutical compositions containing the derivatives or their pharmaceutically acceptable salts, and methods of their use.
Factor Xa is a member of the trypsin-like serine protease class of enzymes. A one-to-one binding of factors Xa and Va with calcium ions and phospholipid forms the prothrombinase complex which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin which polymerizes to form insoluble fibrin.
In the coagulation cascade, the prothrombinase complex is the convergent point of the intrinsic (surface activated) and extrinsic (vessel injury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363; and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulation cascade has been refined further with the discovery of the mode of action of tissue factor pathway inhibitor (TFPI) (Seminars in Hematology (1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serine protease inhibitor with three kunitz-like domains which competes with factor Va for free factor Xa. Once formed, the binary complex of factor Xa and TFPI becomes a potent inhibitor of the factor VIIa and tissue factor complex.
Factor Xa can be activated by two distinct complexes, by tissue factor-VIIa complex on the xe2x80x9cXa burstxe2x80x9d pathway and by the factor IXa-VIIIA complex (TENase) of the xe2x80x9csustained Xaxe2x80x9d pathway in the coagulation cascade. After vessel injury, the xe2x80x9cXa burstxe2x80x9d pathway is activated via tissue factor (TF). Up regulation of the coagulation cascade occurs via increased factor Xa production via the xe2x80x9csustained Xaxe2x80x9d pathway. Down regulation of the coagulation cascade occurs with the formation of the factor Xa-TFPI complex, which not only removes factor Xa but also inhibits further factor formation via the xe2x80x9cXa burstxe2x80x9d pathway. Therefore, the coagulation cascade is naturally regulated by factor Xa.
The primary advantage of inhibiting factor Xa over thrombin in order to prevent coagulation is the focal role of factor Xa versus the multiple functions of thrombin. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, factor VIII to VIIIA, factor V to Va, and factor XI to XIa, but also activates platelets, is a monocyte chemotactic factor, and mitogen for lymphocytes and smooth muscle cells. Thrombin activates protein C, the in vivo anti-coagulant inactivator of factors Va and VIIIa, when bound to thrombomodulin. In circulation, thrombin is rapidly inactivated by antithrombin III (ATIII) and heparin cofactor II (HCII) in a reaction which is catalyzed by heparin or other proteolycan-associated glycosaminoglycans, whereas thrombin in tissues is inactivated by the protease, nexin. Thrombin carries out its multiple cellular activation functions through a unique xe2x80x9ctethered ligandxe2x80x9d thrombin receptor (Cell (1991), Vol. 64, p. 1057), which requires the same anionic binding site and active site used in fibrinogen binding and cleavage and by thrombomodulin binding and protein C activation. Thus, a diverse group of in vivo molecular targets compete to bind thrombin and the subsequent proteolytic events will have very different physiological consequences depending upon which cell type and which receptor, modulator, substrate or inhibitor binds thrombin.
Published data with the proteins antistasin and tick anti-coagulant peptide (TAP) demonstrate that factor Xa inhibitors are efficacious anti-coagulants (Thrombosis and Haemostasis (1992), Vol. 67, pp. 371-376; and Science (1990), Vol. 248, pp. 593-596).
The active site of factor Xa can be blocked by either a mechanism-based or a tight binding inhibitor (a tight binding inhibitor differs from a mechanism-based inhibitor by the lack of a covalent link between the enzyme and the inhibitor). Two types of mechanism-based inhibitors are known, reversible and irreversible, which are distinguished by ease of hydrolysis of the enzyme-inhibitor link (Thrombosis Res (1992), Vol. 67, pp. 221-231; and Trends Pharmacol. Sci. (1987), Vol. 8, pp. 303-307). A series of guanidino compounds are examples of tight-binding inhibitors (Thrombosis Res. (1980), Vol. 19, pp. 339-349). Arylsulfonyl-arginine-piperidinecarboxylic acid derivatives have also been shown to be tight-binding inhibitors of thrombin (Biochem. (1984), Vol. 23, pp. 85-90), as well as a series of arylamidine-containing compounds, including 3-amidinophenylaryl derivatives (Thrombosis Res. (1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones (Thrombosis Res. (1980), Vol. 17, pp. 545-548). However, these compounds demonstrate poor selectivity for factor Xa.
European Published Patent Application 0 540 051 (Nagahara et al.) describes aromatic amidine derivatives which are stated to be capable of showing a strong anticoagulant effect through reversible inhibition of factor Xa.
The synthesis of xcex1,xcex1xe2x80x2-bis(amidinobenzylidene)cycloalkanones and xcex1,xcex1xe2x80x2-bis(amidino-benzyl)cycloalkanones is described in Pharmazie (1977), Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as being serine protease inhibitors.
This invention is directed to compounds or their pharmaceutically acceptable salts which inhibit human factor Xa and are therefore useful as pharmacological agents for the treatment of disease-states characterized by thrombotic activity.
Accordingly, in one aspect, this invention provides compounds selected from the group consisting of the following formulae: 
wherein
A is xe2x80x94C(R11)xe2x95x90 or xe2x80x94Nxe2x95x90;
Z1 and Z2 are independently xe2x80x94Oxe2x80x94, xe2x80x94N(R8)xe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94OCH2xe2x80x94;
R1 and R3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, xe2x80x94N(R8)R9, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94C(O)N(R8)CH2C(O)N(R8)R9, xe2x80x94N(R8)C(O)N(R8)R9, xe2x80x94N(R8)C(O)R8, xe2x80x94N(R8)S(O)2R8, or xe2x80x94N(R8)C(O)N(R8)CH2C(O)N(R8)R9;
R2 is hydrogen; halo; alkyl; haloalkoxy; xe2x80x94OR8; xe2x80x94C(O)OR8; xe2x80x94C(O)N(R8)R9; xe2x80x94N(R8)R9; xe2x80x94C(O)N(R8)(CH2)mC(O)OR8 (where m is 0 to 3); xe2x80x94N(R8)(CH2)nC(O)OR8 (where n is 1 to 3); xe2x80x94N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3); xe2x80x94O(CH2)nC(O)N(R8)R9 (where n is 1 to 3); xe2x80x94O(CH2)pC(O)OR8 (where p is 1 to 6); xe2x80x94N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3); 4-morpholinyl; 3-tetrahydrofuranoxy;
or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of xe2x80x94OR8, xe2x80x94C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl));
or R2 is 1-piperazinyl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
or R2 is 1-piperidinyl (optionally substituted by one or more substituents selected from the group consisting of carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkylcarbonyl, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, and tetrazolylalkyl);
or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl and aralklyl);
or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkyl, aralkyl, amidino, 1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl and alkoxycarbonylalkyl);
R4 and R7 are independently hydrogen, halo, alkyl, nitro, xe2x80x94OR8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94N(R8)R9, xe2x80x94N(H)C(O)R8, or xe2x80x94N(H)S(O)2R8;
R5 is xe2x80x94C(NH)NH2, xe2x80x94C(NH)NHOR8, xe2x80x94C(NH)N(H)C(O)OR8, or xe2x80x94C(NH)N(H)C(O)R8;
R6 is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino, xe2x80x94OR8, xe2x80x94C(NH)NH2, xe2x80x94C(NH)NHOH, xe2x80x94C(O)R10, xe2x80x94(CH2)mC(O)N(R8)R9 (where m is 0 to 3), xe2x80x94CH(OH)C(O)N(R8)R9, xe2x80x94(CH2)mN(R8)R9 (where m is 0 to 3), xe2x80x94(CH2)mC(O)OR8 (where m is 0 to 3), xe2x80x94N(H)C(O)R8, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
each R8 and R9 is independently hydrogen, alkyl, aryl, or aralkyl;
R10 is hydrogen, alkyl, aryl, aralkyl, 1-pyrrolidinyl, 4-morpolinyl, 4-piperazinyl, 4-(N-methyl)piperazinyl, or 1-piperidinyl; and
R11 is hydrogen, alkyl or halo;
or a pharmaceutically acceptable salt thereof.
In another aspect, this invention provides compositions useful in treating a human having a disease-state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound of the invention as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another aspect, this invention provides a method of treating a human having a disease-state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above.
In another aspect, this invention provides a method of treating a human having a disease-state alleviated by the inhibition of factor Xa, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above.
In another aspect, this invention provides a method of inhibiting human factor Xa in vitro or in vivo by the administration of a compound of the invention.
Definitions
As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:
xe2x80x9cHaloxe2x80x9d refers to bromo, chloro or fluoro.
xe2x80x9cAminocarbonylxe2x80x9d refers to the radical xe2x80x94C(O)NH2.
xe2x80x9cAmidinoxe2x80x9d refers to the radical xe2x80x94C(NH)xe2x80x94NH2.
xe2x80x9cBenzamidinexe2x80x9d refers to a phenyl radical substituted by an amidino radical.
xe2x80x9cCarboxyxe2x80x9d refers to the radical xe2x80x94C(O)OH.
xe2x80x9cDimethylaminocarbonylxe2x80x9d refers to the radical xe2x80x94C(O)N(CH3)2.
xe2x80x9cAlkylxe2x80x9d refers to a straight or branched chain monovalent or divalent radical consisting solely of carbon and hydrogen, containing no unsaturation and having from one to six carbon atoms, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.
xe2x80x9cAlkenylxe2x80x9d refers to a straight or branched chain monovalent or divalent radical consisting solely of carbon and hydrogen, containing at least one double bond and having from one to six carbon atoms, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like.
xe2x80x9cHaloalkylxe2x80x9d refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
xe2x80x9cHaloalkoxyxe2x80x9d refers to a radical of the formula xe2x80x94ORb wherein Rb is haloalkyl as defined above, e.g., trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy, and the like.
xe2x80x9cArylxe2x80x9d refers to a phenyl or naphthyl radical optionally substituted by halo, alkyl, alkoxy, nitro or carboxy.
xe2x80x9cAralkylxe2x80x9d refers to a radical of the formula xe2x80x94RaRc where Ra is alkyl as defined above and Rc is aryl as defined above, e.g., benzyl.
xe2x80x9cAryloxyxe2x80x9d refers to a radical of the formula xe2x80x94ORc where Rc is aryl as defined above, e.g., phenoxy and naphthoxy.
xe2x80x9cAlkoxyxe2x80x9d refers to a radical of the formula xe2x80x94ORa where Ra is alkyl as defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (t-butoxy), and the like.
xe2x80x9cAlkanolxe2x80x9d refers to a branched or unbranched aliphatic hydrocarbon of 1 to 6 carbons wherein one hydroxyl radical is attached thereto, e.g., methanol, ethanol, isopropanol, and the like.
xe2x80x9cAminocarbonylalkylxe2x80x9d refers to a radical of the formula xe2x80x94RaC(O)NH2 wherein Ra is alkyl as defined above, e.g., aminocarbonylmethyl, 2-aminocarbonylethyl, 3-aminocarbonylpropyl, 1,1-dimethyl-2-aminocarbonylethyl, and the like.
xe2x80x9c(Alkylamino)carbonylalkylxe2x80x9d refers to a radical of the formula xe2x80x94RaC(O)N(H)Ra wherein each Ra is the same or different and is alkyl as defined above, e.g., (methylamino)carbonylmethyl, 2-(ethylamino)carbonylethyl, 3-(methylamino)carbonylpropyl, 1,1-dimethyl-2-(ethylamino)carbonylethyl, and the like.
xe2x80x9c(Dialkylamino)carbonylalkylxe2x80x9d refers to a radical of the formula carbonylpropyl, xe2x80x94RaC(O)N(Ra)2 wherein each Ra is the same or different and is alkyl as defined above, e.g., (dimethylamino)carbonylmethyl, 2-(diethylamino)carbonylethyl, 3-(dimethylamino)carbonylpropyl, 1,1-dimethyl-2-(diethylamino)carbonylethyl, and the like.
xe2x80x9c(Arylamino)carbonylalkylxe2x80x9d refers to a radical of the formula xe2x80x94RaC(O)N(H)Rc wherein Ra is alkyl as defined above and Rc is aryl as defined above, e.g., phenylaminocarbonylmethyl, 2-phenylaminocarbonylethyl, 3-phenylaminocarbonylpropyl, 1,1-dimethyl-2-phenylaminocarbonylethyl, and the like.
xe2x80x9c(Aralkylamino)carbonylalkylxe2x80x9d refers to a radical of the formula xe2x80x94RaC(O)N(H)Rc wherein Ra is alkyl as defined above and Rd is aralkyl as defined above, e.g., benzylaminocarbonylmethyl, 2-benzylaminocarbonylethyl, 3-benzylaminocarbonylpropyl, 1,1-dimethyl-2-benzylaminocarbonylethyl, and the like.
xe2x80x9cAlkoxycarbonylalkenylxe2x80x9d refers to a radical of the formula xe2x80x94ReC(O)ORa wherein Ra is lower alkyl as defined above and Re is alkenyl as defined above, e.g., 2-methoxycarbonylethenyl, 3-methoxycarbonyprop-1-enyl, 2-ethoxycarbonylethenyl, and the like.
xe2x80x9cCarboxyalkenylxe2x80x9d refers to a radical of the formula xe2x80x94ReC(O)OH where Re is alkenyl as defined above, e.g., 2-carboxyethenyl, 3-carboxyprop-1-enyl, 4-carboxybut-1-enyl, and the like.
xe2x80x9cAminocarbonylalkenylxe2x80x9d refers to a radical of the formula xe2x80x94ReC(O)NH2 wherein Re is alkenyl as defined above, e.g., 2-aminocarbonylethenyl, 3-aminocarbonylprop-1-enyl, 1,1-dimethyl-2-aminocarbonylethenyl, and the like.
xe2x80x9c(Alkylamino)carbonylalkenylxe2x80x9d refers to a radical of the formula xe2x80x94ReC(O)N(H)Ra wherein Ra is alkyl as defined above and Re is alkenyl as defined above, e.g., 2-(ethylamino)carbonylethenyl, 3-(methylamino)carbonylprop-1-enyl, 1,1-dimethyl-2-(ethylamino)carbonylethenyl, and the like.
xe2x80x9c(Dialkylamino)carbonylalkenylxe2x80x9d refers to a radical of the formula xe2x80x94ReC(O)N(Ra)2 wherein Ra is alkyl as defined above and Re is alkenyl as defined above, e.g., 2-(diethylamino)carbonylethenyl, 3-(dimethylamino)carbonylprop-1-enyl, 1,1-dimethyl-2-(diethylamino)carbonylethenyl, and the like.
xe2x80x9c(Arylamino)carbonylalkenylxe2x80x9d refers to a radical of the formula xe2x80x94ReC(O)N(H)Rc wherein Rc is aryl as defined above and Re is alkenyl as defined above, e.g., 2-(phenylamino)carbonylethenyl, 3-(phenylamino)carbonylprop-1-enyl, 1,1-dimethyl-2-(phenylamino)carbonylethenyl, and the like.
xe2x80x9c(Aralkylamino)carbonylalkenylxe2x80x9d refers to a radical of the formula xe2x80x94ReC(O)N(H)Rd wherein Rd is aralkyl as defined above and Re is alkenyl as defined above, e.g., 2-(benzylamino)carbonylethenyl, 3-(benzylamino)carbonylprop-1-enyl, 1,1-dimethyl-2-(benzylamino)carbonylethenyl, and the like.
xe2x80x9c(Hydroxyalkoxy)carbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)ORa(OH) wherein Ra is alkyl as defined above, e.g., 2-(hydroxy)ethoxycarbonyl, 3-(hydroxy)propoxycarbonyl, 5-(hydroxy)pentoxycarbonyl, and the like.
xe2x80x9c(Alkoxy)alkoxycarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)ORaORa wherein each Ra is the same or different and is alkyl as defined above, e.g., 2-(methoxy)ethoxycarbonyl, 3-(methoxy)propoxycarbonyl, 5-(ethoxy)pentoxycarbonyl, and the like.
xe2x80x9c(Hydroxyalkoxy)alkoxycarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)ORaORa(OH), wherein each Ra is the same or different and is alkyl as defined above, e.g., 2-(2-hydroxyethoxy)ethoxycarbonyl, 2-(3-methoxypropoxy)ethoxycarbonyl, and the like.
xe2x80x9c((Alkoxy)alkoxy)alkoxycarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)ORa(ORaORa) where each Ra is the same or different and is alkyl as defined above, e.g., 2-(2-(methoxy)ethoxy)ethoxycarbonyl, 3-(2-(methoxy)ethoxy)propoxycarbonyl, 4-(3-ethoxy)propoxy)butoxycarbonyl, and the like.
xe2x80x9cHaloalkoxycarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)ORb wherein Rb is haloalkyl as defined above, e.g., trifluoromethoxycarbonyl, difluoromethoxycarbonyl, trichloromethoxycarbonyl, 2-trifluoroethoxycarbonyl, 1-fluoromethyl-2-fluoroethoxycarbonyl, 3-bromo-2-fluoropropoxycarbonyl, 1-bromomethyl-2-bromoethoxycarbonyl, and the like.
xe2x80x9cCarboxyalkylxe2x80x9d refers to a radical of the formula xe2x80x94RaC(O)OH where Ra is alkyl as defined above, e.g., carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)ORa wherein Ra is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and the like.
xe2x80x9cAlkoxycarbonylalkylxe2x80x9d refers to a radical of the formula xe2x80x94RaC(O)ORa wherein each Ra is alkyl as defined above, e.g., methoxycarbonylethyl, ethoxycarbonylethyl, t-butoxycarbonylethyl, and the like.
xe2x80x9cMorpholin-4-ylalkylxe2x80x9d refers to a radical of the formula xe2x80x94RaRf where Ra is alkyl as defined above and Rf is a morpholin-4-yl radical, e.g., morpholin-4-ylmethyl, morpholin-4-ylethyl, and the like.
xe2x80x9c4-morpholinoylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)Rf where Rf is a morpholin-4-yl radical.
xe2x80x9c(3,4)-Piperidinyloxyxe2x80x9d refers to a radical of the formula xe2x80x94ORg where Rg is a piperidinyl radical attached to the oxygen atom at either the 3- or 4-position.
xe2x80x9c3-Tetrahydrofuranyloxyxe2x80x9d refers to the radical of the formula xe2x80x94ORh where Rh is a tetrahydrofuranyl radical attached to the oxygen atom at the 3-position.
xe2x80x9c3-Pyrrolidinyloxyxe2x80x9d refers to the radical of the formula xe2x80x94ORi where Ri is a pyrrolidinyl radical attached to the oxygen atom at the 3-position.
xe2x80x9c1-Piperazinoylxe2x80x9d refers to the radical of the formula xe2x80x94C(O)Rj where Rj is 1-piperazinyl.
xe2x80x9c1-Piperidinoylxe2x80x9d refers to the radical of the formula xe2x80x94C(O)Rk where Rk is 1-piperidinyl.
xe2x80x9c1-Pyrrolidinoylxe2x80x9d refers to the radical of the formula xe2x80x94C(O)Rm where Rm is 1-pyrrolidinyl.
xe2x80x9c(1,2)-Imidazolylxe2x80x9d refers to an imidazolyl radical attached at either the 1- or 2-position.
xe2x80x9c(1,2)-Imidazolinylxe2x80x9d refers to a 4,5-dihydroimidazolyl radical attached at either the 1- or the 2-position.
xe2x80x9cDMSOxe2x80x9d refers to dimethyl sulfoxide.
xe2x80x9cHPLCxe2x80x9d refers to high pressure liquid chromatography.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, xe2x80x9coptionally substituted arylxe2x80x9d means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d includes both acid and base addition salts.
xe2x80x9cPharmaceutically acceptable acid addition saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
xe2x80x9cPharmaceutically acceptable base addition saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine.
xe2x80x9cTherapeutically effective amountxe2x80x9d refers to that amount of a compound of formula (I) which, when administered to a human in need thereof, is sufficient to effect treatment, as defined below, for disease-states characterized by thrombotic activity. The amount of a compound of formula (I) which constitutes a xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease-state and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein cover the treatment of a disease-state in a human, which disease-state is characterized by thrombotic activity; and include:
(i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it;
(ii) inhibiting the disease-state, i.e., arresting its development; or
(iii) relieving the disease-state, i.e., causing regression of the disease-state.
The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.
The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms in their structure. The compounds of the invention and their pharmaceutically acceptable salts may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of this invention.
The nomenclature used herein is a modified form of the I.U.P.A.C. system wherein the compounds of the invention are named as derivatives of benzamidine. For example, a compound of the invention selected from formula (I), i.e., 
wherein A is xe2x80x94Nxe2x95x90, Z1 and Z2 are both xe2x80x94Oxe2x80x94, R1 and R3 are both fluoro, R2 is methyl, R4 is methoxy, R5 is xe2x80x94C(NH)NH2, R6 is dimethylamino, and R7 is hydrogen, that is, a compound of the following formula: 
is named herein as 4-methoxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-methylpyridin-2-yl)oxy]benzamidine.
Utility and Administration
A. Utility
The compounds of the invention are inhibitors of factor Xa and therefore useful in disease-states characterized by thrombotic activity based on factor Xa""s role in the coagulation cascade (see Background of the Invention above). A primary indication for the compounds is prophylaxis for long term risk following myocardial infarction. Additional indications are prophylaxis of deep vein thrombosis (DVT) following orthopedic surgery or prophylaxis of selected patients following a transient ischemic attack. The compounds of the invention may also be useful for indications in which coumadin is currently used, such as for DVT or other types of surgical intervention such as coronary artery bypass graft and percutaneous transluminal coronary angioplasty. The compounds are also useful for the treatment of thrombotic complications associated with acute promyelocytic leukemia, diabetes, multiple myelomas, disseminated intravascular coagulation associated with septic shock, purpura fulminanas associated infection, adult respiratory distress syndrome, unstable angina, and thrombotic complications associated with aortic valve or vascular prosthesis. The compounds are also useful for prophylaxis for thrombotic diseases, in particular in patients who have a high risk of developing such disease.
In addition, the compounds of the invention are useful as in vitro diagnostic reagents for selectively inhibiting factor Xa without inhibiting other components of the coagulation cascade.
B. Testing
The primary bioassays used to demonstrate the inhibitory effect of the compounds of the invention on factor Xa are simple chromogenic assays involving only serine protease, the compound of the invention to be tested, substrate and buffer (see, e.g., Thrombosis Res. (1979), Vol. 16, pp. 245-254). For example, four tissue human serine proteases can be used in the primary bioassay, free factor Xa, prothrombinase, thrombin (IIa) and tissue plasminogen activator (tPA). The assay for tPA has been successfully used before to demonstrate undesired side effects in the inhibition of the fibrinolytic process (see, e.g., J. Med. Chem. (1993), Vol. 36, pp. 314-319).
Another bioassay useful in demonstrating the utility of the compounds of the invention in inhibiting factor Xa demonstrates the potency of the compounds against free factor Xa in citrated plasma. For example, the anticoagulant efficacy of the compounds of the invention will be tested using either the prothrombin time (PT), or activated partial thromboplastin time (aPTT) while selectivity of the compounds is checked with the thrombin clotting time (TCT) assay. Correlation of the Ki in the primary enzyme assay with the Ki for free factor Xa in citrated plasma will screen against compounds which interact with or are inactivated by other plasma components. Correlation of the Ki with the extension of the PT is a necessary in vitro demonstration that potency in the free factor Xa inhibition assay translates into potency in a clinical coagulation assay. In addition, extension of the PT in citrated plasma can be used to measure duration of action in subsequent pharmacodynamic studies.
For further information on assays to demonstrate the activity of the compounds of the invention, see R. Lottenberg et al., Methods in Enzymology (1981), Vol. 80, pp. 341-361, and H. Ohno et al., Thrombosis Research (1980), Vol. 19, pp. 579-588.
C. General Administration
Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally, topically, transdermally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. Preferably, the composition will be about 5% to 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
The preferred route of administration is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of severity of the disease-state to be treated. For such oral administration, a pharmaceutically acceptable composition containing a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharine, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
Preferably such compositions will take the form of capsule, caplet or tablet and therefore will also contain a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as croscarmellose sodium or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.
The compounds of the invention, or their pharmaceutically acceptable salts, may also be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier that slowly dissolves within the body, e.g., polyoxyethylene glycols and polyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., a compound(s) of the invention (about 0.5% to about 20%), or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington""s Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state alleviated by the inhibition of factor Xa in accordance with the teachings of this invention.
The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. Generally, a therapeutically effective daily dose is from about 0.14 mg to about 14.3 mg/kg of body weight per day of a compound of the invention, or a pharmaceutically acceptable salt thereof; preferably, from about 0.7 mg to about 10 mg/kg of body weight per day; and most preferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day. For example, for administration to a 70 kg person, the dosage range would be from about 10 mg to about 1.0 gram per day of a compound of the invention, or a pharmaceutically acceptable salt thereof, preferably from about 50 mg to about 700 mg per day, and most preferably from about 100 mg to about 500 mg per day.
Of the compounds of the invention as set forth above in the Summary of the Invention, several groups of compounds are preferred.
One preferred group are those compounds selected from formula (I); 
wherein
A is xe2x80x94Nxe2x95x90;
Z1 and Z2 are independently xe2x80x94Oxe2x80x94, xe2x80x94N(R8)xe2x80x94 or xe2x80x94OCH2xe2x80x94;
R1 and R3 are independently hydrogen, fluoro, chloro, haloalkyl, xe2x80x94N(R8)R9, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94N(R8)C(O)N(R8)R9, xe2x80x94N(R8)C(O)R8, or xe2x80x94N(R8)S(O)2R8;
R2 is hydrogen; halo; alkyl; haloalkoxy; xe2x80x94OR8; xe2x80x94C(O)OR8; xe2x80x94C(O)N(R8)R9; xe2x80x94N(R8)R9; xe2x80x94C(O)N(R8)(CH2)mC(O)OR8 (where m is 0 to 3); xe2x80x94N(R8)(CH2)nC(O)OR8 (where n is 1 to 3); xe2x80x94N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3); xe2x80x94O(CH2)nC(O)N(R8)R9 (where n is 1 to 3); xe2x80x94O(CH2)pC(O)OR8 (where p is 1 to 6); xe2x80x94N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3); 4-morpholinyl; 3-tetrahydrofuranoxy;
or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of xe2x80x94OR8, xe2x80x94C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl));
or R2 is 1-piperazinyl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
or R2 is 1-piperidinyl (optionally substituted by one or more substituents selected from the group consisting of carboxy, carboxyalkyl, alkoxycarbonyl, or alkoxycarbonylalkyl);
or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkylcarbonyl, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, or tetrazolylalkyl);
or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl or aralklyl);
or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkyl, aralkyl, amidino, 1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl);
R4 is hydrogen, xe2x80x94OR8 or xe2x80x94N(R8)R9;
R5 is xe2x80x94C(NH)NH2;
R6 is guanidino, xe2x80x94C(NH)NH2, xe2x80x94C(O)N(R8)R9, xe2x80x94CH(OH)C(O)N(R8)R9, xe2x80x94(CH2)mN(R8)R9 (where m is 0 to 3), 1-piperidinoyl, 1-pyrrolidinoyl, (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
R7 is hydrogen, halo, alkyl, xe2x80x94OR8, xe2x80x94C(O)N(R8)R9; and
R8 and R9 are independently hydrogen, methyl, ethyl or phenyl.
Of this group of compounds, a preferred subgroup of compounds is that subgroup wherein
Z1 and Z2 are independently xe2x80x94Oxe2x80x94 or xe2x80x94NCH3xe2x80x94;
R1 and R3 are independently hydrogen, fluoro, chloro, trifluoromethyl, amino, xe2x80x94C(O)N(R8)R9, or xe2x80x94NHC(O)NHR9;
R2 is hydrogen; alkyl; haloalkoxy; xe2x80x94OR8; xe2x80x94C(O)OR8; xe2x80x94N(R8)R9; xe2x80x94N(R8)(CH2)nC(O)OR8 (where n is 1 to 3); xe2x80x94N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3); xe2x80x94O(CH2)nC(O)N(R8)R9 (where n is 1 to 3); xe2x80x94O(CH2)pC(O)OR8 (where p is 1 to 6); xe2x80x94N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3); 4-morpholinyl; 3-tetrahydrofuranoxy;
or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of xe2x80x94OR8, xe2x80x94C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl));
or R2 is 1-piperazinyl (optionally gubgtituted by one or more substituents independently selected from the group consisting of alkyl, carboxyalkyl, and alkoxycarbonylalkyl);
or R2 is 1-piperidinyl (optionally substituted by one or more substituents selected from the group consisting of carboxy and alkoxycarbonyl);
or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of carboxyalkyl and alkoxycarbonylalkyl);
or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of carboxyalkyl, alkoxycarbonylalkyl and aralklyl);
or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of 1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl and alkoxycarbonylalkyl);
R4 is hydrogen, amino, hydroxy, or methoxy;
R5 is xe2x80x94C(NH)NH2;
R6 is guanidino, xe2x80x94C(NH)NH2, xe2x80x94C(O)N(R8)R9, xe2x80x94(CH2)mN(R8)R9 (where m is 0 to 1), (1,2)-imidazolyl substituted by alkyl, or 2-imidazolinyl substituted by alkyl; R7 is hydrogen, methoxy, or hydroxy; and
R8 and R9 are independently hydrogen, methyl, ethyl, or phenyl.
Of this subgroup of compounds, a preferred class of compounds is that class wherein Z1 and Z2 are both xe2x80x94Oxe2x80x94; R1 and R3 are independently hydrogen, fluoro, or chloro; R4 is amino, hydrogen, hydroxy or methoxy; R6 is guanidino, xe2x80x94C(NH)NH2, xe2x80x94C(O)N(R8)R9, xe2x80x94(CH2)mN(R8)R9 (where m is 0 or 1), (1,2)-imidazolyl substituted by methyl, or 2-imidazolinyl optionally substituted by methyl; and R7 is hydrogen or hydroxy.
Of this class of compounds, a preferred subclass of compounds is that subclass wherein R4 is hydroxy; R6 is dimethylamino or dimethylaminocarbonyl; and R7 is hydrogen.
Of this subclass of compounds, preferred compounds are selected from the following:
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonylmethylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-propoxy-pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-dimethylaminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1,3-difluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-bromo-3-fluoroprop-2-oxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methylpyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((methyl)(carboxymethyl)amino)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-methoxypyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(piperidin-1-yl)-pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(morpholin-4-yl)-pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxymethylpiperazinyl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-ethoxycarbonylmethylpiperazinyl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(4-carboxy-2-(morpholin-4-ylmethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(methyl)-(carboxymethyl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(aminocarbonylmethoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-carboxymethoxypyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(2-dimethylaminoethyl)(carboxymethyl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(pyrrolidin-3-yloxy)pyridin-2-yl]oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-ethoxycarbonylmethylpyrrolidin-3-yloxy)pyridin-2-yl]oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-(1-(1-iminoethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-4-((1-carboxymethyl)pyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine; and
4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminophenoxy)-4-(methyl)-((carboxymethyl)aminocarbonylmethyl)aminopyridin-2-yl)oxy]benzamidine.
Another preferred subclass of compounds is that subclass wherein wherein R4 is hydroxy; R6 is (1,2)-imidazolyl substituted by methyl or 2-imidazolinyl substituted by methyl; and R7 is hydrogen.
Of this subclass, preferred compounds are selected from the following:
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(methyl)-(carboxymethyl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(methyl)(ethoxycarbonylmethyl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(1-(methoxy-carbonyl)ethyl)piperidin-4-yl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-(ethoxycarbonyl)ethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-(2-carboxyethenyl)phenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(1-(ethoxycarbonyl)ethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-hydroxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,3-dimethoxy-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(1-methylimidazolin-2-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-4-(3-(1-methylimidazolin-2-yl)phenoxy)-6-(3,5-dicarboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxy-5-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-hydroxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-amidinophenoxy)-4-(2-methoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-5-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-chloro-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2, 6-dimethyl-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-((1-ethoxycarbonylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-(ethoxycarbonylmethyl)piperazin-1-yl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxycarbonylpiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxypiperidin-1-yl)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-(2-ethoxycarbonylethyl)phenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-ethoxycarbonylmethylphenoxy)pyridin-2-yl)oxy] benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-4-carboxymethylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-(tetrazol-5-yl)phenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-dimethylaminoethyl)(carboxymethyl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethyylpiperidin-4-yl)(methyl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-carboxymethylpiperidin-4-yl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-ethoxycarbonylmethylpiperidin-4-yl)(methyl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-(ethoxycarbonylmethyl)piperidin-4-yl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(piperidin-4-yl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-benzylpiperidin-4-yl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(piperidin-4-yl)(methyl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(1-benzyl-piperidin-4-yl)(methyl)aminopyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(5-carboxypent-1-oxy)pyridin-2-yl)oxy]benzamidine; and
4-hydroxy-3-[(3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine.
Another preferred subclass of compounds is that subclass wherein R4 is hydroxy; R6 is guanidino; and R7 is hydrogen.
Of this subclass of compounds, preferred compounds are selected from the following:
4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-((1-ethoxycarbonylmethyl)piperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(1-carboxymethylpiperidin-4-yloxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(5-ethoxycarbonylpyrrolidin-3-yloxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-methoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-guanidino)phenoxy)-4-(2,6-dimethoxy-4-ethoxycarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-carboxyphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2,6-dimethoxy-4-aminocarbonylphenoxy)pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(2-methoxy-4-carboxyphenoxy)-pyridin-2-yl)oxy]benzamidine;
4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(methyl)(phenyl)aminocarbonylpyridin-2-yl)oxy]benzamidine; and
4-hydroxy-3-[(3,5-difluoro-6-(3-(guanidino)phenoxy)-4-(4-carboxymethylpiperazin-1-yl)pyridin-2-yl)oxy]benzamidine.
Another preferred group of compounds are selected from formula (VII): 
wherein
Z1 and Z2 are independently xe2x80x94Oxe2x80x94, xe2x80x94N(R8)xe2x80x94 or xe2x80x94OCH2xe2x80x94;
R1 and R3 are independently hydrogen, fluoro, chloro, haloalkyl, xe2x80x94N(R8)R9, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94N(R8)C(O)N(R8)R9, xe2x80x94N(R8)C(O)R8, or xe2x80x94N(R8)S(O)2R8;
R2 is hydrogen; halo; alkyl; haloalkoxy; xe2x80x94OR8; xe2x80x94C(O)OR8; xe2x80x94C(O)N(R8)R9; xe2x80x94N(R8)R9; xe2x80x94C(O)N(R8)(CH2)mC(O)OR8 (where m is 0 to 3); xe2x80x94N(R8)(CH2)nC(O)OR8 (where n is 1 to 3); xe2x80x94N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3); xe2x80x94O(CH2)nC(O)N(R8)R9 (where n is 1 to 3); xe2x80x94O(CH2)pC(O)OR8 (where p is 1 to 6); xe2x80x94N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3); 4-morpholinyl; 3-tetrahydrofuranoxy;
or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of xe2x80x94OR8, xe2x80x94C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl));
or R2 is 1-piperazinyl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl);
or R2 is 1-piperidinyl (optionally substituted by one or more substituents selected from the group consisting of carboxy, carboxyalkyl, alkoxycarbonyl, or alkoxycarbonylalkyl);
or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkylcarbonyl, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, or tetrazolylalkyl);
or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl or aralklyl);
or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkyl, aralkyl, amidino, 1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl);
R4 is hydrogen, xe2x80x94OR8 or xe2x80x94N(R8)R9;
R5 is xe2x80x94C(NH)NH2;
R6 is guanidino, xe2x80x94C(NH)NH2, xe2x80x94C(O)N(R8)R9, xe2x80x94CH(OH)C(O)N(R8)R9, xe2x80x94(CH2)mN(R8)R9 (where m is 0 to 3), 1-piperidinoyl, 1-pyrrolidinoyl, (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
R7 is hydrogen, halo, alkyl, xe2x80x94OR8, xe2x80x94C(O)N(R8)R9; and
R8 and R9 are independently hydrogen, methyl, ethyl or phenyl.
Of this group of compounds, a preferred subgroup of compounds is that subgroup wherein
Z1 and Z2 are independently xe2x80x94Oxe2x80x94 or xe2x80x94NCH3xe2x80x94;
R1 and R3 are independently hydrogen, fluoro, chloro, trifluoromethyl, amino, xe2x80x94C(O)N(R8)R9, or xe2x80x94NHC(O)NHR9;
R2 is hydrogen; alkyl; haloalkoxy; xe2x80x94OR8; xe2x80x94C(O)OR8; xe2x80x94N(R8)R9; xe2x80x94N(R8)(CH2)nC(O)OR8 (where n is 1 to 3); xe2x80x94N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3); xe2x80x94O(CH2)nC(O)N(R8)R9 (where n is 1 to 3); xe2x80x94O(CH2)pC(O)OR8 (where p is 1 to 6); xe2x80x94N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3); 4-morpholinyl; 3-tetrahydrofuranoxy;
or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of xe2x80x94OR8, xe2x80x94C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl));
or R2 is 1-piperazinyl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxyalkyl, and alkoxycarbonylalkyl);
or R2 is 1-piperidinyl (optionally substituted by one or more substituents selected from the group consisting of carboxy and alkoxycarbonyl);
or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of carboxyalkyl and alkoxycarbonylalkyl);
or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of carboxyalkyl, alkoxycarbonylalkyl and aralklyl);
or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of 1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl and alkoxycarbonylalkyl);
R4 is hydrogen, amino, hydroxy, or methoxy;
R5 is xe2x80x94C(NH)NH2;
R6 is guanidino, xe2x80x94C(NH)NH2, xe2x80x94C(O)N(R8)R9, xe2x80x94(CH2)mN(R8)R9 (where m is 0 to 1), (1,2)-imidazolyl substituted by alkyl, or 2-imidazolinyl substituted by alkyl; R7 is hydrogen, methoxy, or hydroxy; and
R8 and R9 are independently hydrogen, methyl, ethyl, or phenyl.
Of this subgroup of compounds, a preferred class of compounds is that class wherein Z1 and Z2 are both xe2x80x94Oxe2x80x94; R1 and R3 are independently hydrogen, fluoro, or chloro; R4 is amino, hydrogen, hydroxy or methoxy; R6 is guanidino, xe2x80x94C(NH)NH2, xe2x80x94C(O)N(R8)R9, xe2x80x94(CH2)mN(R8)R9 (where m is 0 or 1), (1,2)-imidazolyl substituted by methyl, or 2-imidazolinyl optionally substituted by methyl; and R7 is hydrogen or hydroxy.
Of this class of compounds, a preferred subclass of compounds is that subclass wherein R4 is hydroxy; R6 is dimethylamino or dimethylaminocarbonyl; and R7 is hydrogen.
Of this subclass of compounds, preferred compounds are 4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonylphenoxy)-2-methoxypyridin-4-yl)-oxy]benzamidine and 4-hydroxy-3-[(3,5-difluoro-6-(3-dimethylaminocarbonyl-phenoxy)-2-(2-methoxy-5-ethoxycarbonylphenoxy)pyridin-4-yl)oxy]benzamidine.
Preparation of Compounds of the Invention
As a matter of convenience, the following description of the preparation of the compounds of the invention is directed to the preparation of compounds of formula (I). It is understood, however, that similar synthetic processes may be used to prepare the compounds of formula (II), (III), (IV), (V), (VI), (VII) and (VIII). It is also understood that in the following description, combinations of substituents and/or variables (e.g., R4 and R5) on the depicted formulae are permissible only if such combinations result in stable compounds.
A. Preparation of Intermediates
1. Compounds of formula (C)
Compounds of formula (C), as shown below, are intermediates in the preparation of the compounds of the invention. As illustrated below in Reaction Scheme 1, compounds of formula (C) are prepared from compounds of formulae (A) and (B) wherein X is chloro or fluoro and R2a is xe2x80x94N(R8)R9, xe2x80x94N(R8)(CH2)mC(O)OR8 (where m is 0 to 3) or piperazinyl (optionally substituted by alkyl, carboxy, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl); and each R8 and R9 is independently hydrogen, alkyl, aryl or aralkyl: 
Compounds of formula (A) and (B) can be prepared according to methods known to those of ordinary skill in the art or are commercially available, for example, from Aldrich Chemical Company, Inc. or from Maybridge Co.
In general, compounds of formula (C) are prepared by reacting a compound of formula (A) with an equimolar amount of a compound of formula (B) at 0xc2x0 C. to 40xc2x0 C., preferably at ambient temperature, in the presence of a base, e.g., triethylamine, or in the presence of a second equivalent of the compounds of formula (B). The compounds of formula (C) are isolated from the resulting reaction mixture by conventional methods.
2. Compounds of formula (F)
Compounds of formula (F), as shown below, are also intermediates in the preparation of the compounds of the invention. As illustrated below in Reaction Scheme 2, compounds of formula (F) are prepared from compounds of formulae (D) and (E) where each X is independently chloro or fluoro; and R2 is alkoxy, haloalkoxy, xe2x80x94O(CH)pC(O)OR8 (where p is 1 to 6), xe2x80x94N(R8)R9, xe2x80x94N(R8)(CH2)nC(O)OR8 (where n is 1 to 3), xe2x80x94N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3), 4-morpholinyl, 3-tetrahydrofuranyloxy; or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of xe2x80x94OR8, xe2x80x94C(O)N(R8)R9, halo, alkyl, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylallcenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl)); or R2 is 1-piperidinyl (optionally substituted by alkoxycarbonyl or alkoxycarbonylalkyl); or R2 is 1-piperazinyl (optionally substituted by alkyl, alkoxycarbonyl or alkoxycarbonylalkyl); or R2 is (3,4)-piperidinyloxy (optionally substituted by alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl or tetrazolylalkyl); or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by alkyl, alkoxycarbonyl, alkoxycarbonylalkyl or aralklyl); or R2 is 3-pyrrolidinyloxy (optionally substituted by alkyl, aralkyl or alkoxycarbonylalkyl); and each R8 and R9 is independently hydrogen, alkyl, aryl or aralkyl: 
Compounds of formulae (D) and (E) are commercially available or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (F) are prepared by treating a compound of formula (D) with a compound of formula (E) in an aprotic solvent, for example, methylene chloride, at between about 0xc2x0 C. and 50xc2x0 C., preferably at ambient temperature, and, if the hydrogen in the compound of formula (E) is an hydroxyl hydrogen, in the presence of a base, for example, cesium carbonate. The compound of formula (F) is isolated from the reaction mixture by standard techniques.
3. Compounds of formulae (J) and (K)
Compounds of formulae (J) and (K), as shown below, are also intermediates in the preparation of the compounds of the invention. As illustrated below in Reaction Scheme 3, compounds of formula (J) and (K) are prepared from compounds of formula (G) and formula (H) where A is xe2x80x94Nxe2x95x90 or xe2x80x94C(R11)xe2x95x90 (where R11 is hydrogen, alkyl or halo); X is fluoro of chloro; R1 and R3 are independently hydrogen, halo, alkyl haloalkyl, alkoxy, haloalkoxy, nitro, xe2x80x94N(R8)R9, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94C(O)N(R8) CH2C(O)N(R8)R9, xe2x80x94N(R8)C(O)N(R8)R9, xe2x80x94N(R8)C(O)R8, xe2x80x94N(R8)S(O)2R8, or xe2x80x94N(R8) C(O)N(R8)CH2xe2x80x94C(O)N(R8)R9; R2 is hydrogen, alkyl, haloalkoxy, xe2x80x94OR8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94N(R8)R9, xe2x80x94C(O)N(R8)(CH2)mC(O)OR8 (where m is 0 to 3), xe2x80x94N(R8) (CH2)nC(O)OR8 (where n is 1 to 3), xe2x80x94N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3), xe2x80x94O(CH2)nC(O)N(R8)R9 (where n is 1 to 3), xe2x80x94O(CH2)pC(O)OR8 (where p is 1 to 6), xe2x80x94N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3), 4-morpholinyl, 3-tetrahydrofuranoxy; or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of xe2x80x94OR8, xe2x80x94C(O)N(R8)R9, halo, alkyl, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl)); or R2 is 1-piperazinyl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is 1-piperidinyl (optionally substituted by one or more substituents selected from the group consisting of alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, and tetrazolylalkyl); or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, alkoxycarbonylalkyl and aralklyl); or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkyl, aralkyl, alkoxycarbonyl and alkoxycarbonylalkyl); R4 is independently hydrogen, halo, alkyl, nitro, xe2x80x94OR8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94N(R8)R9, or xe2x80x94N(H)C(O)R8; and each R8 and R9 is independently hydrogen, alkyl, aryl or aralkyl: 
Compounds of formula (G) include compounds of formulae (C) and (F) as described above, or may be prepared by methods described herein or by methods known to one of ordinary skill in the art. They may also be commercially available, for example, from Aldrich Chemical Co., Inc. or from Maybridge Co. Compounds of formula (H) may be prepared by methods known to one of ordinary skill in the art or may be commercially available, for example, from Aldrich Chemical Co., Inc.
In general, the compounds of formulae (J) and (K) are prepared by reacting a compound of formula (G) with a compound of formula (H) (in an equimolar amount for a compound of formula (K) and with two or more equivalents of a compound of formula (H) for a compound of formula (J)) in the presence of a base, e.g., sodium hydride or cesium carbonate, at temperatures between about 20xc2x0 C. and 120xc2x0 C., preferably, for compounds of formula (J), at temperatures of around 100xc2x0 C., in an aprotic solvent, for example, dimethylformamide, DMSO or acetonitrile, for a period of time sufficient to complete the desired reaction as monitored by thin layer chromatography (TLC). Compounds of formulae (J) and (K) are then isolated from the reaction mixture by standard isolation techniques.
In a similar manner, compounds of formula (G) may be treated with compounds of formula (H) wherein the hydroxy group is replaced by an amino group to produce compounds of formulae (J) and (K) wherein the ether connecting group is replaced by an amino connecting group. The amino group can then be alkylated by standard procedures.
Compounds of formulae (J) and (K) wherein R4 is an amino group may be further treated with an alkylsulfonyl halide, e.g., methylsulfonylchloride, under basic conditions at ambient temperature to produce compounds of formulae (J) and (K) wherein R4 is xe2x80x94N(H)S(O)2R8.
4. Compounds of formula (M)
Compounds of formula (M), as shown below, are also intermediates in the preparation of the compounds of the invention. As illustrated below in Reaction Scheme 4, compounds of formula (M) are prepared from compounds of formula (K) and formula (L) where A is xe2x80x94Nxe2x95x90 or xe2x80x94C(R11)xe2x95x90 (where R11 is hydrogen, alkyl or halo); X is fluoro of chloro; R1 and R3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, xe2x80x94N(R8)R9, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94C(O)N(R8)CH2C(O)N(R8)R9, or xe2x80x94N(R8)C(O)N(R8)CH2C(O)N(R8)R9; R2 is hydrogen, alkyl, haloalkoxy, xe2x80x94OR8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94N(R8)R9, xe2x80x94C(O)N(R8)(CH2)mC(O)OR8 (where m is 0 to 3), xe2x80x94N(R8)(CH2)nC(O)OR8 (where n is 1 to 3), xe2x80x94N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3), xe2x80x94O(CH2)nC(O)N(R8)R9 (where n is 1 to 3), xe2x80x94O(CH2)pC(O)OR8 (where p is 1 to 6), xe2x80x94N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3), 4-morpholinyl, 3-tetrahydrofuranoxy; or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of xe2x80x94OR8, xe2x80x94C(O)N(R8)R9, halo, alkyl, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl)); or R2 is 1-piperazinyl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is 1-piperidinyl (optionally substituted by one or more substituents selected from the group consisting of alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, and tetrazolylalkyl); or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, alkoxycarbonylalkyl and aralklyl); or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkyl, aralkyl, alkoxycarbonyl and alkoxycarbonylalkyl); R4 and R7 are independently hydrogen, halo, alkyl, nitro, xe2x80x94OR8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94N(R8)R9, or xe2x80x94N(H)C(O)R8; R6 is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino, xe2x80x94OR8, xe2x80x94C(NH)NH2, xe2x80x94C(NH)NHOH, xe2x80x94C(O)R10, xe2x80x94(CH2)mC(O)N(R8)R9 (where m is 0 to 3), xe2x80x94CH(OH)C(O)N(R8)R9, xe2x80x94(CH2)mN(R8)R9 (where m is 0 to 3), xe2x80x94(CH2)mC(O)OR8 (where m is 0 to 3), xe2x80x94N(H)C(O)R8, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl); and each R8 and R9 is independently hydrogen, alkyl, aryl, or aralkyl: 
Compounds of formula (K) are prepared according to the methods described herein (see Reaction Scheme 3 above). Compounds of formula (L) are commercially available, for example, from Aldrich Chemical Co., or from Maybridge Co., or may be prepared according to methods known to those of ordinary skill in the art.
In general, the compounds of formula (M) are prepared in the same manner as described above for compounds of formula (J) and (K).
Compounds of formula (M) where R4 or R7 is hydroxy may be reacted with a haloalkane, such as iodomethane, under standard conditions to produce the corresponding compounds of formula (M) where R4 or R7 is alkoxy.
Compounds of formula (M) where R6 or R7 contains xe2x80x94C(O)OR8 where R8 is alkyl or aryl may be hydrolyzed under basic conditions (for example, in the presence of sodium hydroxide) to produce compounds of formula (M) where R6 or R7 contains xe2x80x94C(O)OR8 where R8 is hydrogen.
Compounds of formula (M) where the ether connecting group has been replaced by an unsubstituted amino connecting group may be treated with an alkylating agent, such as iodomethane, in the presence of a base, to produce compounds of formula (M) wherein the amino connecting group is substituted by alkyl, aryl, or aralkyl. In addition, compounds of formula (K) can be treated with a compound of formula (L) wherein the hydroxy group is replaced by a hydroxymethyl (xe2x80x94CH2OH) group to produce the corresponding compounds of formula (M).
Compounds of formula (M) where each R6 and R7 independently contains xe2x80x94C(O)OR8 where R8 is hydrogen may be amidated or esterified under standard conditions to produce compounds of formula (M) where R6 or R7 contains xe2x80x94C(O)OR8 where R8 is alkyl, aryl or aralkyl, or compounds of formula (M) where R6 or R7 contains xe2x80x94C(O)N(R8)R9 where R8 and R9 are independently hydrogen, alkyl, aryl or aralkyl.
Compounds of formula (M) where R3 is nitro may be reduced under standard conditions to produce compounds of formula (M) where R3 is amino; which can then be reacted with the appropriate acid halide or aryl- or alkylsulfonyl halide to produce compounds of formula (M) where R3 is xe2x80x94N(R8)C(O)R8 or xe2x80x94N(R8)S(O)2R8 where R8 is defined above. In addition, compounds of formula (M) where R3 is amino can be reacted with an isocyanate or chloroformate to produce compounds of formula (M) where R3 is xe2x80x94N(R8)C(O)N(R8)R9 or xe2x80x94N(R8)C(O)OR8.
5. Compounds of formula (P)
Compounds of formula (P), as shown below, are also intermediates in the preparation of the compounds of the invention, particularly those compounds of formula (I) wherein A is xe2x80x94C(R11)xe2x95x90. As illustrated below in Reaction Scheme 5, compounds of formula (P) are prepared from compounds of formulae (N) and (O) where X is fluoro or chloro; R1 and R3 are independently hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, xe2x80x94N(R8)R9, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94C(O)N(R8)CH2C(O)N(R8)R9, xe2x80x94N(R8)C(O)N(R8)R9, xe2x80x94N(R8)C(O)R8, xe2x80x94N(R8)S(O)2R8, or xe2x80x94N(R8)C(O)N(R8)CH2xe2x80x94C(O)N(R8)R9; R2 is hydrogen, alkyl, haloalkoxy, xe2x80x94OR8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94N(R8)R9, xe2x80x94C(O)N(R8)(CH2)mC(O)OR8 (where m is 0 to 3), xe2x80x94N(R8) (CH2)nC(O)OR8 (where n is 1 to 3), xe2x80x94N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3), xe2x80x94O(CH2)nC(O)N(R8)R9 (where n is 1 to 3), xe2x80x94O(CH2)pC(O)OR8 (where p is 1 to 6), xe2x80x94N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3), 4-morpholinyl, 3-tetrahydrofuranoxy; or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of xe2x80x94OR8, xe2x80x94C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl)); or R2 is 1-piperazinyl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is 1-piperidinyl (optionally substituted by one or more substituents selected from the group consisting of carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkylcarbonyl, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, and tetrazolylalkyl); or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl and aralklyl); or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkyl, aralkyl, amidino, 1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl and alkoxycarbonylalkyl); each R8 and R9 is independently hydrogen, alkyl, aryl, or aralkyl; and R11 is hydrogen, alkyl or halo: 
Compounds of formulae (M) and (O) may be prepared according to ordinary skill in the art, or by methods described herein, or may be commercially available, for example, from Aldrich Chemical Co., Inc.
In general, compounds of formula (P) are prepared in the same manner as described above for compounds of formula (J), except the temperatures at which the reaction is run are elevated to between about 50xc2x0 C. and 130xc2x0 C. The compounds of formula (P) are isolated from the reaction mixture by conventional techniques.
B. Preparation of the Compounds of the Invention
In the following Reaction Scheme 6, compounds of formula (Ia) are compounds of formula (I) as described above in the Summary of the Invention wherein Z1 and Z2 are xe2x80x94Oxe2x80x94. As illustrated below in Reaction Scheme 6, wherein A is xe2x80x94Nxe2x95x90 or xe2x80x94C(R11)xe2x95x90 (where R11 is hydrogen, alkyl or halo); R1 and R3 is hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, xe2x80x94N(R8)R9, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94C(O)N(R8)CH2C(O)N(R8)R9, xe2x80x94N(R8)C(O)N(R8)R9, xe2x80x94N(R8)C(O)R8, xe2x80x94N(R8)S(O)2R8, or xe2x80x94N(R8)C(O)N (R8)CH2xe2x80x94xe2x80x94C(O)N(R8)R9; R2 is hydrogen, alkyl, haloalkoxy, xe2x80x94OR8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94N(R8)R9, xe2x80x94C(O)N(R8)(CH2)mC(O)OR8 (where m is 0 to 3), xe2x80x94N(R8)(CH2)nC(O)OR8 (where n is 1 to 3), xe2x80x94N((CH2)nN(R8)R9)(CH2)nC(O)OR8 (where each n is 1 to 3), xe2x80x94O(CH2)nC(O)N(R8)R9 (where n is 1 to 3), xe2x80x94O(CH2)pC(O)OR8 (where p is 1 to 6), xe2x80x94N(R8)(CH2)nC(O)N(R8)(CH2)nC(O)OR8 (where each n is independently 1 to 3), 4-morpholinyl, 3-tetrahydrofuranoxy, or R2 is aryloxy (optionally substituted by one or more substituents independently selected from the group consisting of xe2x80x94OR8, xe2x80x94C(O)N(R8)R9, halo, alkyl, carboxy, alkoxycarbonyl, haloalkoxy, haloalkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, (alkylamino)carbonylalkyl, (dialkylamino)carbonylalkyl, (arylamino)carbonylalkyl, (aralkylamino)carbonylalkyl, alkoxycarbonylalkenyl, carboxyalkenyl, aminocarbonylalkenyl, (alkylamino)carbonylalkenyl, (dialkylamino)carbonylalkenyl, (arylamino)carbonylalkenyl, (aralkylamino)carbonylalkenyl, (hydroxyalkoxy)carbonyl, (alkoxy)alkoxycarbonyl, (hydroxyalkoxy)alkoxycarbonyl, ((alkoxy)alkoxy)alkoxycarbonyl, tetrazolyl, morpholin-4-ylalkyl, and (1,2)-imidazolinyl (optionally substituted by alkyl)); or R2 is 1-piperazinyl (optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is 1-piperazinoyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is 1-piperidinyl (optionally substituted by one or more substituents selected from the group consisting of carboxy, carboxyalkyl, alkoxycarbonyl, and alkoxycarbonylalkyl); or R2 is (3,4)-piperidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkylcarbonyl, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, and tetrazolylalkyl); or R2 is piperidin-4-ylamino (wherein the amino is optionally substituted by alkyl and the piperidinyl group is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl and aralklyl); or R2 is 3-pyrrolidinyloxy (optionally substituted by one or more substituents selected from the group consisting of alkyl, aralkyl, amidino, 1-iminoethyl, carboxy, carboxyalkyl, alkoxycarbonyl and alkoxycarbonylalkyl); R4 and R7 are independently hydrogen, halo, alkyl, nitro, xe2x80x94OR8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)R9, xe2x80x94N(R8)R9, or xe2x80x94N(H)C(O)R8; R6 is halo, alkyl, haloalkyl, haloalkoxy, nitro, amino, ureido, guanidino, xe2x80x94OR8, xe2x80x94C(NH)NH2, xe2x80x94C(NH)NHOH, xe2x80x94C(O)R10, xe2x80x94(CH2)mC(O)N(R8)R9 (where m is 0 to 3), xe2x80x94CH(OH)C(O)N(R8)R9, xe2x80x94(CH2)mN(R8)R9 (where m is 0 to 3), xe2x80x94(CH2)mC(O)OR8 (where m is 0 to 3), xe2x80x94N(H)C(O)R8, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl); each R8 and R9 is independently hydrogen, alkyl, aryl, or aralkyl; and R10 is hydrogen, alkyl, aryl, aralkyl, 1-pyrrolidinyl, 4-morpholinyl, 4-piperazinyl, 4-(N-methyl)piperazinyl, or 1-piperidinyl; compounds of formula (Ia) are prepared from compounds of formula (Q) as follows: 
Compounds of formula (Q) are prepared as described herein above for compounds of formulae (J), (M), and (P).
In general, compounds of formula (Ia) are prepared from compounds of formula (Q) by dissolving the compound of formula (Q) in an anhydrous alkanol, preferably ethanol and then treating the solution with an anhydrous mineral acid, preferably HCl, while maintaining the reaction temperatures between about xe2x88x9278xc2x0 C. and ambient temperature for between 2 hours and 24 hours, allowing the temperature to rise to ambient temperature while monitoring for reaction completion, for example, through thin layer chromatography. The solvent is then removed and the resulting residue dissolved in fresh anhydrous alkanol, preferably ethanol. The resulting solution was then treated with anhydrous ammonia at ambient pressure or in a sealed flask, at temperatures from between ambient temperature and 100xc2x0 C. for about 1 to about 5 hours. The compounds of formula (Ia) are then isolated from the reaction mixture by standard techniques.
Compounds of formula (Ia) wherein R6 is xe2x80x94C(NH)NH2 or xe2x80x94C(NH)NHOH are produced from the corresponding cyano compounds.
Compounds of formula (Ia) wherein R1, R2 or R3 contains xe2x80x94C(O)N(R8)R9 or xe2x80x94C(O)OR8 where each R8 and R9 are independently alkyl, haloalkyl, aryl or aralkyl may be hydrolyzed under acidic conditions to prepare compounds of formula (Ia) where R1, R2 or R3 contains xe2x80x94C(O)OR8 where R8 is hydrogen.
Under the same conditions as previously described, compounds of formula (Ia) where R1, R2 or R3 contains xe2x80x94C(O)OR8 where R8 is hydrogen, alkyl, aryl or aralkyl, may be amidated to form compounds of formula (Ia) where R1, R2 or R3 contains xe2x80x94C(O)N(R8)R9 where R8 and R9 are independently hydrogen, alkyl, aryl or aralkyl.
Compounds of formula (Ia) where R4 is xe2x80x94OR8 where R8 is alkyl, aryl or aralkyl, may be converted to compounds of formula (Ia) where R4 is xe2x80x94OR8 where R8 is hydrogen by treatment with boron tribromide in an aprotic solvent, for example, methylene chloride, at temperatures at first between xe2x88x9280xc2x0 C. and 0xc2x0 C., then at ambient temperature, for about 4 hours to about 16 hours.
Alternatively, compounds of formula (Ia) where R4 is xe2x80x94OR8 where R8 is arylmethyl, preferably, benzyl, may be treated with hydrogen and the appropriate catalyst, for example, palladium on carbon, to give compounds of formula (Ia) where R4 is xe2x80x94OR8 where R8 is hydrogen.
Compounds of formula (Ia) where R2 is 3-pyrrolidinyloxy substituted by arylmethyl on the nitrogen may be treated under standard hydrogenolysis conditions to remove the arylmethyl group to produce compounds of formula (Ia) where R2 is unsubstituted 3-pyrrolidinyloxy, which can then be reacted with the appropriate imidate to produce the compounds of formula (Ia) where R2 is 3-pyrrolidinyloxy substituted by 1-iminoethyl, or with the appropriate haloalkyl esters to produce the compounds of formula (Ia) where R2 is 3-pyrrolidinyloxy substituted by alkoxycarbonylalkyl.
In summary, compounds of the invention, are prepared by:
1) reacting a compound of formula (A) as described above with a compound of formula (B) as described above under the conditions as described above to produce a compound of formula (C) as described above, which is an intermediate in the preparation of the compounds of the invention; or
2) reacting a compound of formula (D) as described above with a compound of formula (E) as described above under conditions as described above to produce a compound of formula (F) as described above, which is an intermediate in the preparation of the compounds of the invention; or
3) reacting a compound of formula (G) as described above, which can be a compound of formula (C) as described above or a compound of formula (F) as described above, with a compound of formula (H) as described above under conditions as described above to produce a compound of formula (J) or a compound of formula (K) as described above, which are intermediates in the preparation of the compounds of the invention; then
4) reacting a compound of formula (K) as described above with a compound of formula (L) as described above under conditions as described above to produce a compound of formula (M) as described above, which is an intermediate in the preparation of the compounds of the invention; or
5) reacting a compound of formula (N) as described above with a compound of formula (O) as described above under conditions as described above to produce a compound of formula (P) as described above, which is an intermediate in the preparation of the compounds of the invention: then
6) reacting a compound of formula (Q) as described above, which can be a compound of formula (J), a compound of formula (M) or a compound of formula (P) as described above, with the appropriate reagent under the conditions as described above to form compounds of formula (Ia) as described above.
Similar reactions may be performed on similar starting materials and intermediates to produce the corresponding compounds of the inventions not depicted in the Reaction Schemes above.
In addition, all compounds of the invention that exist in free base form or free acid form may be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic acid, or by the appropriate inorganic or organic base. Salts of the compounds of the invention can also be converted to the free base form or to the free acid form or to another salt.